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Fibroblast growth factor receptor type 4 as a potential therapeutic target in clear cell renal cell carcinoma

BACKGROUND: Several clear cell renal cell carcinoma (ccRCC) cases harbour fibroblast growth factor receptor 4 (FGFR4) gene copy number (CN) gains. In this study, we investigated the functional contribution of FGFR4 CN amplification in ccRCC. METHODS: The correlation between FGFR4 CN determined via r...

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Autores principales: Narisawa, Takafumi, Naito, Sei, Ito, Hiromi, Ichiyanagi, Osamu, Sakurai, Toshihiko, Kato, Tomoyuki, Tsuchiya, Norihiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9942348/
https://www.ncbi.nlm.nih.gov/pubmed/36803783
http://dx.doi.org/10.1186/s12885-023-10638-3
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author Narisawa, Takafumi
Naito, Sei
Ito, Hiromi
Ichiyanagi, Osamu
Sakurai, Toshihiko
Kato, Tomoyuki
Tsuchiya, Norihiko
author_facet Narisawa, Takafumi
Naito, Sei
Ito, Hiromi
Ichiyanagi, Osamu
Sakurai, Toshihiko
Kato, Tomoyuki
Tsuchiya, Norihiko
author_sort Narisawa, Takafumi
collection PubMed
description BACKGROUND: Several clear cell renal cell carcinoma (ccRCC) cases harbour fibroblast growth factor receptor 4 (FGFR4) gene copy number (CN) gains. In this study, we investigated the functional contribution of FGFR4 CN amplification in ccRCC. METHODS: The correlation between FGFR4 CN determined via real-time PCR and protein expression evaluated using western blotting and immunohistochemistry was assessed in ccRCC cell lines (A498, A704, and 769-P), a papillary RCC cell line (ACHN), and clinical ccRCC specimens. The effect of FGFR4 inhibition on ccRCC cell proliferation and survival was assessed via either RNA interference or using the selective FGFR4 inhibitor BLU9931, followed by MTS assays, western blotting, and flow cytometry. To investigate whether FGFR4 is a potential therapeutic target, a xenograft mouse model was administered BLU9931. RESULTS: 60% of ccRCC surgical specimens harboured an FGFR4 CN amplification. FGFR4 CN was positively correlated with its protein expression. All ccRCC cell lines harboured FGFR4 CN amplifications, whereas ACHN did not. FGFR4 silencing or inhibition attenuated intracellular signal transduction pathways, resulting in apoptosis and suppressed proliferation in ccRCC cell lines. BLU9931 suppressed tumours at a tolerable dose in the mouse model. CONCLUSION: FGFR4 contributes to ccRCC cell proliferation and survival following FGFR4 amplification, making it a potential therapeutic target for ccRCC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-023-10638-3.
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spelling pubmed-99423482023-02-22 Fibroblast growth factor receptor type 4 as a potential therapeutic target in clear cell renal cell carcinoma Narisawa, Takafumi Naito, Sei Ito, Hiromi Ichiyanagi, Osamu Sakurai, Toshihiko Kato, Tomoyuki Tsuchiya, Norihiko BMC Cancer Research BACKGROUND: Several clear cell renal cell carcinoma (ccRCC) cases harbour fibroblast growth factor receptor 4 (FGFR4) gene copy number (CN) gains. In this study, we investigated the functional contribution of FGFR4 CN amplification in ccRCC. METHODS: The correlation between FGFR4 CN determined via real-time PCR and protein expression evaluated using western blotting and immunohistochemistry was assessed in ccRCC cell lines (A498, A704, and 769-P), a papillary RCC cell line (ACHN), and clinical ccRCC specimens. The effect of FGFR4 inhibition on ccRCC cell proliferation and survival was assessed via either RNA interference or using the selective FGFR4 inhibitor BLU9931, followed by MTS assays, western blotting, and flow cytometry. To investigate whether FGFR4 is a potential therapeutic target, a xenograft mouse model was administered BLU9931. RESULTS: 60% of ccRCC surgical specimens harboured an FGFR4 CN amplification. FGFR4 CN was positively correlated with its protein expression. All ccRCC cell lines harboured FGFR4 CN amplifications, whereas ACHN did not. FGFR4 silencing or inhibition attenuated intracellular signal transduction pathways, resulting in apoptosis and suppressed proliferation in ccRCC cell lines. BLU9931 suppressed tumours at a tolerable dose in the mouse model. CONCLUSION: FGFR4 contributes to ccRCC cell proliferation and survival following FGFR4 amplification, making it a potential therapeutic target for ccRCC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-023-10638-3. BioMed Central 2023-02-20 /pmc/articles/PMC9942348/ /pubmed/36803783 http://dx.doi.org/10.1186/s12885-023-10638-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Narisawa, Takafumi
Naito, Sei
Ito, Hiromi
Ichiyanagi, Osamu
Sakurai, Toshihiko
Kato, Tomoyuki
Tsuchiya, Norihiko
Fibroblast growth factor receptor type 4 as a potential therapeutic target in clear cell renal cell carcinoma
title Fibroblast growth factor receptor type 4 as a potential therapeutic target in clear cell renal cell carcinoma
title_full Fibroblast growth factor receptor type 4 as a potential therapeutic target in clear cell renal cell carcinoma
title_fullStr Fibroblast growth factor receptor type 4 as a potential therapeutic target in clear cell renal cell carcinoma
title_full_unstemmed Fibroblast growth factor receptor type 4 as a potential therapeutic target in clear cell renal cell carcinoma
title_short Fibroblast growth factor receptor type 4 as a potential therapeutic target in clear cell renal cell carcinoma
title_sort fibroblast growth factor receptor type 4 as a potential therapeutic target in clear cell renal cell carcinoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9942348/
https://www.ncbi.nlm.nih.gov/pubmed/36803783
http://dx.doi.org/10.1186/s12885-023-10638-3
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